The overall objective of this proposal is to examine the evolutionary consequences of introducing a tetravalent live-attenuated dengue virus vaccine into children in Northern Thailand on naturally occurring endemic wild-type dengue virus. Dengue virus has evolved over the last 200 years as four distinct serotypes and an important human pathogen producing severe illness known as dengue hemorrhagic fever (DHF). Dengue is considered an emerged global public health problem. It is the most common arbovirus causing human disease in subtropical and tropical regions of the world and estimated that over 50 million DV infections occur each year with several hundred thousand cases of DHF, and over 20,000 deaths. DHF is a major cause of hospitalization and disability adjusted life-years (DALYs). A dengue vaccine that offers protection against all four dengue serotypes is a high priority and based on cost per DALYs saved, highly cost- effective. It is not known what the effects of vaccination will do on the evolution of naturally occurring dengue viruses. Vaccination may create an environment of relative low-transmission of natural dengue virus, within the human host and its vector, thereby increasing stochastic events that will allow new dengue virus genotypes to emerge. In this application, an experienced interdisciplinary team of university and military investigators in the US and Thailand proposes to conduct coordinated studies to determine the effect vaccination with a candidate live-attenuated tetravalent vaccine will have on vaccine related genetic changes on wild-type dengue virus and how these changes will determine risk for DHF in hospitalized children, serotype-specific dengue virus transmission in the vaccinated and surrounding population, and in its mosquito vector. Coordinated studies will be performed during the vaccine trial in Kamphaeng Phet Province, Northern Thailand, to isolate wild-type dengue virus and examine genetic diversity in the population, in hospitalized children with severe dengue illness and cluster investigation of their neighborhoods, and through integrated intensive vector surveillance, in the vector population. The field testing of the first dengue vaccine efficacy study offers a unique opportunity to study the evolutionary consequences of this vaccine on wild-type dengue virus with findings that will have long-term impact on the design of future dengue vaccines and conduct of dengue vaccine efficacy trials. PUBLIC HEALTH RELEVANCE: This research proposal involves studies in the United States and Thailand to understand how the tetravalent live-attenuated dengue vaccine will affect the evolution of naturally occurring wild-type dengue virus in a country endemic for dengue.